Endogenously produced nitric oxide (NO) is believed to produce a variety of effects in vivo, including reducing inflammation, regulating blood flow, and fighting microbial infection. Exogenously provided NO gas has also been described in the treatment of infection, to prevent biofilm formation, to increase the rate of wound re-epithelialization, and to rapidly close diabetic foot ulcers.
The potential therapeutic usefulness of NO has led to the search for solid-phase nitric oxide donors, including those capable of controlled NO release. See Keefer, L. K., Chemtech 28, 30-35 (1998). Several small molecule NO donors have been reported, the most notable being N-diazeniumdiolates. For example, small molecule N-diazeniumdiolate NO donors can be synthesized by the reaction of amines with NO at elevated pressure and have been used, for example, to spontaneously generate NO in aqueous solution. See Hrabie, J. A. and Keefer, L. K., Chem. Rev. 102, 1135-1154 (2002).
Macromolecular NO-releasing scaffolds have also been described, including NO-releasing dendrimers (see Stasko, N. A., and Schoenfisch, M. H., J. Am. Chem. Soc. 128, 8265-8271 (2006)), NO-releasing gold nanoparticles (see Rothrock, A. R., et al., J. Am. Chem. Soc. 127, 9362-9363 (2005)), and NO-releasing silica nanoparticles. See Shin J. H. et al., J. Am. Chem. Soc. 129, 4612-4619 (2007). A recent report describes the antibacterial activity of NO-releasing xerogel film. See Hetrick, E. M. and Schoenfisch, M. H., Biomaterials 28, 1948-1956 (2007).
Antibiotic resistance has caused bacterial infections to become the most common cause of infectious disease-related death. See Robson, M. C. (1977) Surg. Clin. N. Am. 77, 637-650. Antibiotic-resistant pathogens are the primary reason for a majority of all lethal nosocomial infections. The growing danger of life-threatening infections and the rising economic burden of resistant bacteria have created a demand for new antibacterial therapeutics. The present invention provides a new therapy for the treatment of microbial infections.